Rheumatoid arthritis (RA) is a chronic debilitating disease affecting over 1% of Americans. Women are affected about 3 times more often than men. RA also constitutes a major health problem among the U.S. Veterans. The Veteran population is aging, and the number of women serving in the military is gradually increasing. In addition, Veterans in combat zones are exposed to extreme stress and toxic substances in different forms. All these factors may directly or indirectly influence host immunity and induction/aggravation of RA. The pain, discomfort, lost working days, and disabilities caused by RA can adversely affect Veterans' quality of life and work in many ways, as well as impose heavy cost of healthcare and rehabilitation. Therefore, studies advancing our understanding of the pathogenesis and treatment of RA are highly relevant to the U.S. Veterans. Two main challenges in the field of arthritis are 1) to define the mechanisms that render the joints highly prone to attack by a systemic autoimmune response, and 2) to devise novel ways to direct systemically-administered drugs primarily into the inflamed joints (without intra-articular injection) to achieve maximum therapeutic effect, but with minimum adverse effects. We hypothesize that the vascular endothelium of the inflamed joints is characterized by unique molecular markers that facilitate both selective migration of pathogenic T cells into the target organ (the arthritic joints) and cellular/ molecular interactions with the mediators of inflammation and bone damage. Furthermore, the targeting of one or more of these vascular endothelial cell markers would offer new therapeutic approaches for downregulating joint inflammation and tissue damage without undue adverse reactions or systemic toxicity. This proposition is based on the results of our recently published study in PNAS on the synovial vasculature in the rat adjuvant arthritis (AA) model of RA, which was done in collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham Institute, La Jolla, CA). The study was aimed at identifying unique arthritic joint-homing peptides using an innovative approach of in vitro and in vivo enrichment of clones from a phage peptide-display library. The advantage of the phage system for the detection of tissue-specific markers is that there is no a priori bias in predicting the ligands that bind to the vascular endothelium. And, unlike antibodies the phage-displayed peptides interact with the functional domain of the target molecule. This approach has been pioneered by Dr. Ruoslahti, who has developed the concept of vascular address molecules or zip codes. His group has examined several organs in this regard, but not the joints. We have now filled this gap by identifying two novel 9-residue peptides (denoted as NQR and ADK) that preferentially home to the inflamed joints and show unique receptor-binding and cellular-signaling attributes compared to the well-known arginine-glycine-aspartic acid (RGD) motif that binds to specific integrins. Furthermore, the treatment of arthritic rats wit NQR peptide attenuated AA, whereas ADK peptide failed to do so. The aims of our study are: Aim 1. Use the peptides (NQR and ADK) with a drug for synovial vasculature-targeted delivery into arthritic joints to control inflammation and bone damage. As a proof-of-concept, the drug will be encapsulated in liposomes, whose surface is decorated with NQR/ADK peptide. These joint-homing peptides would direct the liposomes preferentially into the inflamed joints. Liposomes will be treated with polyethylene glycol to inhibit their uptake by the reticuloendothelial system; Aim 2. Define the cellular/molecular events triggered by the joint-homing peptides upon interaction with endothelial cells and to examine the mechanisms underlying the anti-arthritic activity of NQR peptide. We will determine the effect of NQR/ADK peptide on the pathogenic mediators produced by endothelial cells; the gene expression profile of endothelial cells; and the migration of defined subsets of leukocytes. The results of this study would advance our knowledge of the disease process in autoimmune arthritis and help design novel peptide-directed, targeted drug delivery with increased therapeutic index for the treatment of RA.